The focus of this grant is to determine the extent to which muscle supports bone repair. Our long term goal is to better characterize the sources of skeletal stem cells that are required for bone regeneration and to understand how endogenous stem cells are recruited in vivo to participate in repair. We are investigating the role of potential stem cell populations within bone marrow and periosteum, and of other sources such as muscle. The importance of muscle in bone repair is clinically established. Traumatic musculoskeletal injuries not only affect bone itself but also the vasculature and surrounding soft tissues such as muscle. Delayed unions and non-unions can be treated using bone morphogenetic proteins (BMPs), fasciocutaneous and muscle transplants; however, the role of muscle in these surgical interventions is not known. We hypothesize that muscle plays a critical role in bone repair in part by providing a source of vascular cells and skeletal stem/progenitor cells that can be recruited locally in response to BMPs. First, we will determine whether the recruitment of muscle-derived cells can occur physiologically in response to bone injury. We will use genetic tools and mouse models of bone repair to track muscle-derived cells during healing. Second, we will functionally assess the role of muscle in bone repair by analyzing the consequences of muscle obstruction and loss of satellite cells on revascularization of the fracture site, inflammatory response and recruitment of osteoblasts and chondrocytes during bone healing. Third, we will examine the role of BMPs in recruiting cells from muscle during bone repair. Altogether, results from these experiments will provide valuable information to potentially enhance bone repair using muscle-derived cells and to improve existing therapies based on BMPs treatment and muscle transplants. PUBLIC HEALTH RELEVANCE: The clinical importance of muscle and other soft tissues in fracture repair is well recognized, since delayed union or non-union occur in 5 to 10% of all fractures but is increased up to 46% in patients with extreme trauma and soft tissue damage. To determine the functional roles of muscle in bone repair and ultimately improved the use of muscle for fracture repair, this proposal will (i) assess the cellular contribution of muscle to bone repair using in vivo cell tracking in mice, (ii) analyze the consequences of mutations affecting muscle tissue on bone repair and (iii) examine the effects of the clinically approved bone morphogenetic proteins on the recruitment of muscle-derived cells during bone repair.